Arylpiperazine opioid receptor antagonists

ABSTRACT

Provided are opioid receptor antagonists represented by the formula (I): 
                         
where R, Y 3 , R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein.

RELATED APPLICATION INFORMATION

This application is a Divisional of U.S. application Ser. No. 13/574,179filed on Jul. 19, 2012, allowed, which claims priority to U.S.provisional application Ser. Nos. 61/307,534, filed on Feb. 24, 2010,and 61/316,423, filed on Mar. 23, 2010, all incorporated herein byreference.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to 4-arylpiperazine compounds. Thesecompounds function as opioid receptor antagonists, and can be used totreat a variety of disease states.

Description of the Background

The opioid receptors, μ, δ, κ, and the opioid-like receptor ORL-1 belongto the super family of G-protein coupled receptors (GPCRs) that possessseven helical trans-membrane spanning domains in their architecture.¹The majority of research efforts focused upon this group of proteins hasbeen directed toward the preceptor since it mediates the actions of boththe opiate and opioid analgesics such as morphine and fentanyl,respectively.² However, over the years it has become increasingly clearthat the entire family of proteins is actively involved in a host ofbiological processes.² Furthermore, the advent of selective antagonistshas demonstrated that pharmacotherapeutic opportunities exist via bothnegative and positive modulation of this receptor family.³⁻⁸

The opioid receptor system has been extensively studied, and thousandsof compounds have been synthesized and evaluated by in vitro binding andfunctional assays as well as by animal models.² An integral part of theeffort to characterize the opioid receptor system has been the discoveryof potent, pure antagonists. Naloxone (1a) and naltrexone (1b), bothcompetitive antagonists at μ, δ, and κ opioid receptors,⁹ have beenextensively used as pharmacological tools to identify and characterizeopioid systems (see FIG. 1 for structures). Additionally, naloxone isapproved to treat heroin overdose and to reverse respiratory depressioncaused by morphine.⁹ Naltrexone is used to treat heroin and alcoholabuse.

In 1978, Zimmerman and co-workers reported the discovery of astructurally unique series of opioid receptor pure antagonists based onN-substituted analogues of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine(2a, LY272922).¹⁰ Unlike naloxone (1a) and naltrexone (1b) where theantagonist activity is dependent on the N-allyl or N-cyclopropylmethylsubstituent, all N-substitutedtrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2) including theN-methyl analogue 2b are opioid receptor pure antagonists.¹⁰⁻¹⁴ A few ofthe more interesting analogues include alvimopan (3), which is anFDA-approved drug for GI motility disorder,¹⁵ LY255,582 (2d),^(13,16)which was developed to treat obesity, and the selective κ opioidreceptor antagonist JDTic (4),^(6-8,17) which shows activity in ratmodels of depression,¹⁸ anxiety,¹⁹ and stress-induced cocaine relapse.¹⁸JDTic appears to be a promising therapeutic.

Komoto et al. reported structures like 6a-f in a paper entitled “Newμ-Opioid Receptor Agonists with Piperazine Moiety.” They do not describethat the compounds have opioid receptor antagonistic efficacy.²⁰ Thecompounds are synthesized by a route similar to that used to prepare5a-j. At present, the opiate class, represented by naloxone (1a),naltrexone (1b), and the N-substituted3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, represented by alvimopan,LY255,582, and JDTic, are the only two classes of nonpeptide pure opioidreceptor antagonists known. The discovery that 3-[4-(substitutedpiperazine-yl)]phenols (5) as described herein are pure opioid receptorantagonists adds a third example of this important class of compounds.

Studies with selective κ opioid antagonists have shown that this systemis intimately involved in brain processes that relate to stress, fear,and anxiety as well as reward-seeking behavior. Studies have shown thatJDTic (4) and nor-BNI, another κ opioid selective antagonist,dose-dependently reduce fear and stress-induced responses in multiplebehavioral paradigms with rodents (immobility in the forced-swimassay,^(18,21) reduction of exploratory behavior in the elevated plusmaze, and fear-potentiated startle).¹⁹ Furthermore, selective κantagonists have been shown to reduce stress-induced reinstatement ofcocaine self-administration in rats,¹⁸ to block the stress-inducedpotentiation of cocaine place preference conditioning,²²⁻²⁴ to decreasedependence-induced ethanol self-administration,²⁵ to diminishdeprivation-induced eating in rats,²⁶ and to prevent pre-pulseinhibition mediated by U50,488.²⁷ These observations regarding thebehavioral consequences of receptor blockade in several animal testssuggest that κ antagonists will be useful for treating anxiety,depression, schizophrenia, addiction, and eating disorders.

Previously reported non-selective opioid receptor antagonists such asLY255582 have been found to increase metabolic energy consumption andreduce the weight in obese rats while maintaining muscle mass. Thesereports suggest that opioid receptor antagonists may be useful inpreventing, treating, and/or ameliorating the effect of obesity. EliLilly and Company has developed new classes of opioid receptorantagonists that interact with the μ, δ, and κ receptors (termednon-selective) as potential pharmacotherapies to treat obesity andrelated diseases.^(28,29) The Lilly patents suggest that such compoundswill be useful for the treatment and/or prophylaxis of obesity andrelated diseases including eating disorders (bulimia, anorexia nervosa,etc.), diabetes, diabetic complications, diabetic retinopathy,sexual/reproductive disorders, depression, anxiety, epileptic seizure,hypertension, cerebral hemorrhage, congestive heart failure, sleepingdisorders, atherosclerosis, rheumatoid arthritis, stroke,hyperlipidemia, hypertriglycemia, hyperglycemia, hyperlipoproteinemia,substance abuse, drug overdose, compulsive behavior disorders (such aspaw licking in dog), and addictive behaviors such as for examplegambling and alcoholism.

SUMMARY OF THE INVENTION

Aryl-substituted piperazines (5) are a new class of opioid receptorantagonists (see the Examples section below for representativestructures). Similar to the N-substituted3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, even the N-methylsubstituted analog 5f is a pure opioid antagonist. Changing theN-substituent to an N-phenylpropyl group gives 5b, which has K_(e)values of 0.88, 13.4, and 4.09 nM at the μ, δ, and κ opioid receptors,which are similar to the K_(e) values of N-phenylpropyl3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 2c (RTI-5989-264). TheJDTic-like analog from this class 5j has K_(e) values of 22, 274, and2.7 nM at the μ, δ, and k opioid receptors, respectively (see Table 1).All compounds of this class thus far synthesized are relativelynonselective opioid receptor antagonists. Thus, their opioid receptorproperties are more like those of naloxone (1a), naltrexone (1b), andthe originally reported N-substituted3,4-dimethyl-4-(3-hydroxyphenyl)piperidines.¹³

Thus, the present invention is directed to aryl-substituted piperazineopioid receptor antagonists represented by the formula (I):

wherein

R is hydrogen, OH, OC₁₋₆ alkyl, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl substituted by one or more groups Y₁,CH₂-aryl wherein the aryl group is substituted by one or more groups Y₁,OCOC₁₋₈ alkyl, COC₁₋₈ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₈ alkyl, orNHCO₂C₁₋₈ alkyl;

Y₃ is hydrogen, Br, Cl, F, CN, CF₃, NO₂, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂;

R₁, R₂, R₃ and R₄ are each, independently, one of the followingstructures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to form acyclo alkyl group or a bridged heterocyclic ring;

each Y₁ is, independently, hydrogen, OH, Br, Cl, F, CN, CF₃, NO₂, N₃,OR₈, CO₂R₉, C₁₋₆ alkyl, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, orCH₂(CH₂)_(n)Y₂, or two adjacent Y₁ groups form a —O—CH₂—O— or—O—CH₂CH₂—O— group;

each Y₂ is, independently, hydrogen, CF₃, CO₂R₉, C₁₋₈ alkyl, NR₁₀R₁₁,NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, CH₂OH, CH₂OR₈, COCH₂R₉,

each n is, independently, 0, 1, 2 or 3;

each o is, independently, 0, 1, 2 or 3;

each R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ is, independently, hydrogen,C₁₋₈ alkyl, CH₂-aryl wherein the aryl group is substituted by one ormore substituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′;

each Y₂′ is, independently, hydrogen, CF₃, or C₁₋₆ alkyl;

R₅ is

R₆ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₄ alkyl substituted C₄₋₈ cycloalkyl,C₁₋₄ alkyl substituted C₄₋₈ cycloalkenyl, or thiophene;

X is a single bond, —C(O)— or —CH(OR₁₅)—;

R₁₅ hydrogen, C₁₋₆ alkyl, —(CH₂)_(q)-phenyl or —C(O)—R₁₆;

R₁₆ is C₁₋₄ alkyl or —(CH₂)_(q)-phenyl;

each q is, independently, 1, 2 or 3;

R₁₇ is hydrogen, C₁₋₈ alkyl, CO₂C₁₋₈ alkylaryl substituted by one ormore groups Y₁, CH₂-aryl substituted by one or more groups Y₁, orCO₂C₁₋₈ alkyl;

R₁₈ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈ alkynyl, CH₂CO₂C₁₋₈alkyl, CO₂C₁₋₈ alkyl or CH₂-aryl substituted by one or more groups Y₁;

R₁₉ is a group selected from the group consisting of structures (a)-(p):

Q is NR₂₁, CH₂, O, S, SO, or SO₂;

each Y₄ is, independently, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₂₂, CO₂R₂₃,C₁₋₆ alkyl, NR₂₄R₂₅, NHCOR₂₆, NHCO₂R₂₇, CONR₂₈R₂₉, or CH₂(CH₂)_(n)Y₂,

or two adjacent Y₄ groups form a —O—CH₂—O— or —O—CH₂CH₂—O— group;

p is 0, 1, 2, or 3;

R₂₀ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkenyl, CH₂OR₃₀, orCH₂-aryl substituted by one or more substituents Y₁;

each R₂₁ is, independently, hydrogen, C₁₋₈ alkyl, CH₂-aryl substitutedby one or more substituents Y₁, NR₃₁R₃₂, NHCOR₃₃, NHCO₂R₃₄, CONR₃₅R₃₆,CH₂(CH₂)_(n)Y₂, or C(═NH)NR₃₇R₃₈;

R₃₀ is hydrogen C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkenyl, CH₂O₂C₁₋₈ alkyl,CO₂C₁₋₈ alkyl, or CH₂-aryl substituted by one or more substituents Y₁;

R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆,R₃₇ and R₃₈ are, independently, hydrogen, C₁₋₈ alkyl, CH₂-arylsubstituted by one or more substituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃,C₁₋₆ alkyl, or CH₂(CH₂)_(n)Y₂′;

Z is N, O or S, wherein when Z is O or S, there is no R₁₈;

X₁ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl;

X₂ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl;

or X₁ and X₂ together form ═O, ═S, or ═NH,

with the proviso that when R₅ is;

then at least one of R₁, R₂, R₃ and R₄ is other than hydrogen as definedabove;

or a pharmaceutically acceptable salt thereof.

The present invention also includes pharmaceutical compositions, whichcomprise the opioid receptor antagonist described above and apharmaceutically acceptable carrier.

The present invention also includes a method of antagonizing opioidreceptors, comprising administering an effective amount of the opioidreceptor antagonist discussed above to a subject in need thereof.

The present invention also includes a method of treating drug addiction,drug abuse, depression, anxiety, schizophrenia, obesity and eatingdisorders, comprising administering an effective amount of the opioidreceptor antagonist discussed above to a subject in need thereof.

The present invention also includes a method of treating alcoholaddiction, nicotine addiction, cocaine addition and methamphetamineaddiction, comprising administering an effective amount of the opioidreceptor antagonist discussed above to a subject in need thereof.

The present invention also includes a method of treating diabetes,diabetic complications, diabetic retinopathy, sexual/reproductivedisorders, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleeping disorders, atherosclerosis,rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia,hyperglycemia, hyperlipoproteinemia, substance abuse, drug overdose,compulsive behavior disorders and addictive behaviors, comprisingadministering an effective amount of the opioid receptor antagonistdiscussed above to a subject in need thereof.

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following FIGURES in conjunction with thedetailed description below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: chemical structure of compounds 1-6.

DETAILED DESCRIPTION OF THE INVENTION

A broad description of the invention is provided in the Summary sectionabove.

In another embodiment of the invention:

R is hydrogen, OH, OC₁₋₃ alkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, aryl substituted by one or more groups Y₁,CH₂-aryl wherein the aryl group is substituted by one or more groups Y₁,OCOC₁₋₄ alkyl, COC₁₋₄ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₄ alkyl, orNHCO₂C₁₋₄ alkyl; and

Y₃ is hydrogen, Br, Cl, F, CN, CF₃, NO₂, OR₈, CO₂R₉, C₁₋₃ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂;

In another embodiment of the invention, R₁, R₂, R₃ and R₄ are each,independently, one of the following structures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to 5 to 7membered alkyl group or a bridged heterocyclic ring.

In another embodiment of the invention, R₅ is

In another embodiment of the invention, at least one of R₁, R₂, R₃ andR₄ is other than hydrogen.

In another embodiment of the invention, R is hydrogen, OH, OC₁₋₂ alkyl,C₁₋₂ alkyl, C₁₋₂ haloalkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, aryl substitutedby one or more groups Y₁, CH₂-aryl wherein the aryl group is substitutedby one or more groups Y₁, COC₁₋₂ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₂alkyl, or NHCO₂C₁₋₂ alkyl.

In another embodiment of the invention, R is hydrogen, OH, OCH₃, OCF₃,COCH₃, OCOCH₃, CONH₂, NHCHO, NH₂, NHSO₂CH₃, or NHCO₂CH₃.

In another embodiment of the invention, R is hydrogen, OH, OCH₃, orOCF₃.

In another embodiment of the invention, Y₃ is hydrogen.

In another embodiment of the invention, R₁, R₂, R₃ and R₄ are each,independently, one of the following structures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to 5 to 7membered alkyl group or a bridged heterocyclic ring.

In another embodiment of the invention, R₁, R₂, R₃ and R₄ are each,independently, hydrogen, methyl or ethyl.

In another embodiment of the invention, R₁, R₂, R₃ and R₄ are each,independently, hydrogen or methyl.

In another embodiment of the invention, R₁, R₂, R₃ and R₄ are each,independently, hydrogen or methyl, wherein at least one of R₁, R₂, R₃and R₄ is methyl.

In another embodiment of the invention, R₅ is hydrogen, C₁₋₄ alkyl or—(CH₂)_(n)-phenyl.

In another embodiment of the invention, R₅ is

In another embodiment of the invention:

R is hydrogen, OH, OCH₃, or OCF₃;

Y₃ is hydrogen;

R₁, R₂, R₃ and R₄ are each, independently, hydrogen, methyl or ethyl;and

R₅ is hydrogen, C₁₋₄ alkyl or —(CH₂)_(n)-phenyl.

In one preferred embodiment, R₂ is other than hydrogen as defined above.This substitution may increase opioid efficacy by an order of magnitude.The chiralty at the resulting stereocenter may be (R) or (S). Preferredsubstituents are C₁₋₈ alkyl, preferably methyl, ethyl and propyl.

In another embodiment of the invention at least one of R₁, R₂, R₃ and R₄is other than hydrogen as defined above when R₅ is

In another preferred embodiment of the present invention, the opioidreceptor antagonists are as described in the following Examples section.

The present invention includes any and all combination of the differentstructural groups defined above, including those combinations notspecifically set forth above.

As used throughout this disclosure, the terms “alkyl group” or “alkylradical” encompass all structural isomers thereof, such as linear,branched and cyclic alkyl groups and moieties. Unless stated otherwise,all alkyl groups described herein may have 1 to 8 carbon atoms,inclusive of all specific values and subranges therebetween, such as 2,3, 4, 5, 6, or 7 carbon atoms. Representative examples include methyl,ethyl, propyl and cyclohexyl.

As used throughout this disclosure, the terms “haloalkyl group” or“haloalkyl radical” encompass all structural isomers thereof, such aslinear, branched and cyclic groups and moieties. Unless statedotherwise, all haloalkyl groups described herein may have 1 to 8 carbonatoms, inclusive of all specific values and subranges therebetween, suchas 2, 3, 4, 5, 6, or 7 carbon atoms. A C₁₋₂ haloalkyl group isparticularly preferred. At least one hydrogen atom is replaced by ahalogen atom, i.e., fluorine, chlorine, bromine or iodine. In oneembodiment, all of the hydrogen atoms are replaced with halogen atoms.Fluorine is preferred. Perfluoroalkyl groups are particularly preferred.Examples of haloalkyl groups include trifluoromethyl (—CF₃) andperfluoroethyl (—CF₂CF₃).

The alkenyl group or alkynyl group may have one or more double or triplebonds, respectively. As will be readily appreciated, when an alkenyl oralkynyl group is bonded to a heteroatom a double or triple bond is notformed with the carbon atom bonded directly to the heteroatom. Unlessstated otherwise, all alkenyl and alkynyl groups described herein mayhave 2 to 8 carbon atoms, inclusive of all specific values and subrangestherebetween, such as 3, 4, 5, 6, or 7 carbon atoms. Preferred examplesinclude —CH═CH₂, —CH₂CH═CH₂, —CCH and —CH₂CCH.

The aryl group is a hydrocarbon aryl group, such as a phenyl, naphthyl,phenanthryl, anthracenyl group, which may have one or more C₁₋₄ alkylgroup substituents.

The compounds of the present invention may be in the form of apharmaceutically acceptable salt via protonation of the amines with asuitable acid. The acid may be an inorganic acid or an organic acid.Suitable acids include, for example, hydrochloric, hydroiodic,hydrobromic, sulfuric, phosphoric, citric, acetic, fumaric, tartaric,and formic acids.

The opioid receptor selectivity may be determined based on the bindingaffinities at the receptors indicated or their selectivity in opioidfunctional assays.

The compounds of the present invention may be used to bind opioidreceptors. Such binding may be accomplished by contacting the receptorwith an effective amount of the inventive compound. Of course, suchcontacting is preferably conducted in an aqueous medium, preferably atphysiologically relevant ionic strength, pH, etc. Receptor antagonism isthe preferred mode of action of the compounds described herein.

The inventive compounds may also be used to treat patients havingdisease states which are ameliorated by binding opioid receptors or inany treatment wherein temporary suppression of the kappa opioid receptorsystem is desired. Such diseases states include opiate addiction (suchas heroin addiction), cocaine, nicotine, or ethanol addiction. Thecompounds of the present invention may also be used as cytostaticagents, as antimigraine agents, as immunomodulators, asimmunosuppressives, as antiarthritic agents, as antiallergic agents, asvirucides, to treat diarrhea, as antipsychotics, as antischizophrenics,as antidepressants, as uropathic agents, as antitussives, asantiaddictive agents, as anti-smoking agents, to treat alcoholism, ashypotensive agents, to treat and/or prevent paralysis resulting fromtraumatic ischemia, general neuroprotection against ischemic trauma, asadjuncts to nerve growth factor treatment of hyperalgesia and nervegrafts, as anti-diuretics, as stimulants, as anti-convulsants, or totreat obesity. Additionally, the present compounds can be used in thetreatment of Parkinson's disease as an adjunct to L-dopa for treatmentof dyskinesia associated with the L-dopa treatment.

The compounds of the present invention are particularly useful fortreating addiction, such as addiction to cocaine, alcohol,methamphetamine, nicotine, heroine, and other drugs of abuse. Withrespect to nicotine, the compounds of the present invention are alsouseful in treating nicotine withdrawal effects.

The compounds may be administered in an effective amount by any of theconventional techniques well-established in the medical field. Forexample, the compounds may be administered orally, intraveneously, orintramuscularly. When so administered, the inventive compounds may becombined with any of the well-known pharmaceutical carriers andadditives that are customarily used in such pharmaceutical compositions.For a discussion of dosing forms, carriers, additives, pharmacodynamics,etc., see Kirk-Othmer Encyclopedia of Chemical Technology, FourthEdition, Vol. 18, 1996, pp. 480-590, incorporated herein by reference.The patient is preferably a mammal, with human patients especiallypreferred. Effective amounts are readily determined by those of ordinaryskill in the art. Studies by the present inventors show no toxicity andno lethality for the present compounds at amounts up to 300 mg/kg inmice.

The compounds of the present invention can be administered as a singledosage per day, or as multiple dosages per day. When administered asmultiple dosages, the dosages can be equal doses or doses of varyingamount, based upon the time between the doses (i.e. when there will be alonger time between doses, such as overnight while sleeping, the doseadministered will be higher to allow the compound to be present in thebloodstream of the patient for the longer period of time at effectivelevels). Preferably, the compound and compositions containing thecompound are administered as a single dose or from 2-4 equal doses perday.

Suitable compositions containing the present compounds further comprisea physiologically acceptable carrier, such as water or conventionalpharmaceutical solid carriers, and if desired, one or more buffers andother excipients.

The compounds of the invention may be synthesized by, for example, theschemes shown in the following Examples. Those skilled in the art willappreciate that the synthesis of the exemplified compounds can readilybe adapted for the preparation of other compounds within the scope offormula I.

EXAMPLES

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

Chemistry and Biology

Compounds 5a-f of the present invention may be synthesized, for example,in accordance with the reaction sequence shown in Scheme 1. Thetert-butoxycarbonyl-protected starting piperazines 7a-e were prepared bytreating the appropriate piperazine with Boc₂O or Boc-ON using standardconditions. The piperazines required for 7a-d were commerciallyavailable. Piperazine needed for 7e was synthesized according toreported methods.^(1,2) The tert-butoxycarbonyl-protected piperazines7a-e were coupled to 3-bromoanisole under palladium-catalyzed conditionsto give 8a-e. Treatment of 8a-e with boron tribromide in methylenechloride at −78° C. effected removal of the tert-butoxycarbonyl groupand demethylation of the methyl ether to give 9a-e. Reductive alkylationof 9a-e using 3-phenylpropionaldehyde and sodium triacetoxyborohydridein 1,2-dichloroethane yielded the desired 5a-e. Reductive alkylation of9b using formaldehyde and Raney nickel under a hydrogen atmosphereyielded 5f.

Compounds 5g,h can be synthesized by the routes shown in Scheme 2.Compound 10 was coupled to 3-bromoanisole under palladium-catalyzedconditions to give 11. Subjection of 11 to palladium on carbon inrefluxing aqueous acetic acid removed the N-allyl-protecting group togive 12. Treatment of 12 with boron tribromide in methylene chloride at−78° C. affected demethylation of 12 to give the phenol 13. Reductivealkylation of 13 using 3-phenylpropionaldehyde and sodiumtriacetoxyborohydride in 1,2-dichloroethane yielded 6h. Treatment of 10with (Boc₂)O in methylene chloride containing triethylamine gives theN-allyl, N-Boc-protected piperazine 14. Subjection of 14 to palladium oncarbon in refluxing aqueous acetic acid selectively removed the N-allylgroup to give 15. Compound 15 was coupled to 3-bromoanisole underpalladium-catalyzed conditions to yield 16. Treatment of 16 with borontribromide in methylene chloride at −78° C. effected removal of thetert-butoxycarbonyl group and demethylation of the methyl ether to give17. Reductive alkylation of 17 using 3-phenylpropanaldehyde and sodiumtriacetoxyborohydride in 1,2-dichloroethane afforded the desired 5g.

Scheme 3 outlines the synthesis of 5i and 5j. Compound 9b is coupledwith N-Boc-valine using BOP to give an amide which is not isolated butreduced directly to 5i using diborane in tetrahydrofuran. Coupling of 5iwith 7-OH-Boc-D-Tic using BOP in tetrahydrofuran followed by treatmentwith trifluoroacetic acid in methylene chloride yielded 5j.

Biology

Measures of opioid receptor antagonism and specificity were obtained bymonitoring the ability of selected test compounds to inhibit stimulationof [³⁵S]GTPγS binding produced by the selective agonists(D-Ala²,MePhe⁴,Gly-ol⁵)enkephalin (DAMGO, mu receptor)cyclo[D-Pen²,D-Pen⁵]enkephalin (DPDPE, delta) and5,7,8-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide(U69,593, kappa) in cloned human receptors (Table 1).

Results

Compounds 5a-j show high efficacy (low K_(e) values) for the kappaopioid receptor in the [³⁵S]GTPγS in vivo functional assay, particularly5b-e, 5g, and 5j. The compounds of the present invention are potentkappa opioid receptor antagonists in an in vitro functional test. Somecompounds showed good selectivity for the kappa relative to the mu anddelta opioid receptors.

ExperimentalGeneral Procedures for the Preparation of 3-[4-(Substitutedpiperazin-1-yl)]phenols (6a-e)

a. Palladium-catalyzed 3-Methoxyphenylation Procedure. In a thick-walledglass sealable tube, 1 eq of piperazine 7a-c was dissolved in 20 mL ofdry toluene along with 1.5 eq of 3-bromoanisole, 0.005 eq of Pd₂(dba)₃,1.5 eq of KOtBu, and 0.01 eq of P(tBu)₃ as a 1M solution in toluene. Thetube was flushed with argon, sealed, and heated to 110° C. for 16 h. Thevessel was cooled to room temperature, opened, and the contents filteredthrough celite. The filtered solution was reduced to a fifth of itsvolume by evaporation under reduced pressure. The remaining solution wassubjected to column chromatography on silica gel eluting withhexanes-EtOAc (5:1). The combined fractions containing the product weresubjected to rotary evaporation, and the remaining oil was dried underhigh vacuum.

b. Transition Metal-free 3-Methoxyphenylation.³ In a round-bottom flaskequipped with a condenser under an argon dry atmosphere, 1.1 eq ofKN(Si(CH₃)₃)₂ was suspended in 7 mL of dry 1,4-dioxane. The piperazines7d,e, 1 eq, was added followed by 1 eq of 3-bromoanisole. The reactionmixture was stirred at 100° C. for 2.5 h, cooled to room temperature,and quenched with H₂O (10 mL). To the mixture was added Et₂O (15 mL) andshaken vigorously. The layers were separated, and the aqueous layer wasextracted twice with Et₂O (10 mL). The pooled organic solution wasconcentrated by rotary evaporation, and the residue was subjected tocolumn chromatography on silica gel eluting with hexane-EtOAc (5:1). Thecombined fractions containing the product were subjected to rotaryevaporation, and the remaining oil was dried under high vacuum.

c. Removal of the N-Boc and O-Me Protecting Groups with BBr₃. Under anargon atmosphere, 1 eq of Boc-protected phenylpiperazine 8 was dissolvedin CH₂Cl₂ (20 mL), and the solution was cooled to −78° C. Into thismixture, 4 eq of BBr₃ as a 1 M solution in CH₂Cl₂ were introduced. Thereaction mixture was stirred for 4 h, warmed to 0° C., and stirred foran additional 2 h. Into this solution dry MeOH (20 mL) was slowly added,and the solution was stirred for 5 min. The solvents were then removedunder reduced pressure at 25° C. The residue was redissolved in MeOH (20mL), and the solvents were removed again under reduced pressure toafford a residue that was recrystallized or converted to the freebaseand purified by column chromatography on silica gel to yield theproduct.

d. Removal of the N-Boc and O-Me Protecting Groups with Conc. HBr. In around-bottom flask 8 were dissolved in conc. HBr, and the solution wasrefluxed for 16 h. Removal of the solvents by rotary evaporation gave aresidue that was dissolved in MeOH. This solution was stirred overexcess NaHCO₃ for 10 min and then filtered. The solution wasconcentrated under reduced pressure and subjected to columnchromatography on silica gel to afford the product.

e. Reductive Alkylation of 9a-e with 3-Phenylpropanaldehyde. In a dryflask 1 eq of phenylpiperazine 9a-e was dissolved in 1,2-dichloroethane(20 mL) along with 1.5 eq of 3-phenylpropanaldehyde and 1.5 eq of Et₃N.The solution was cooled to 0° C., and 1.5 eq of Na(OAc)₃BH was thenadded. The reaction mixture was stirred for 1 h at 0° C., allowed towarm to 25° C. After stirring for 2 h, the reaction mixture was added toa concentrated solution of NaHCO₃ (20 mL) and shaken vigorously. Thelayers were separated, and the organic layer was washed once with H₂O (5mL) and once with brine (5 mL). The organic solution was dried (MgSO₄),filtered, and the solvents removed under reduced pressure to yield theproduct which was purified as specified.

1-tert-Butoxycarbonyl-4-(3-methoxyphenyl)piperazine (8a). Generalprocedure a. was employed using 0.996 g (5.35 mmol) of commerciallyavailable Boc-piperazine 7a to obtain, after chromatography, 1.53 g(98%) of 8a as a yellowish solid: mp 62-63° C. ¹H NMR (CDCl₃) δ 7.18 (t,1H), 6.54 (m, 1H), 6.46. (s, 1H), 6.45 (m, 1H), 3.79 (s, 3H), 3.57 (m,4H), 3.13 (m, 4H), 1.48 (s, 9H). ESIMS: m/z 293 (M+H⁺, 100).

(S)-tert-Butyl-4-(3-methoxyphenyl)-3-methylpiperazine-1-carboxylate(8b). General procedure a. was employed using 1.32 g (6.60 mmol) ofBoc-piperazine 7b⁴ to obtain, after chromatography, 1.19 g (59%) of 8bas a yellow oil with spectra identical to that of 8c.

(R)-tert-Butyl-4-(3-methoxyphenyl)-3-methylpiperazine-1-carboxylate(8c). General procedure a. was employed using 1.00 g (5.00 mmol) ofBoc-piperazine 7b⁴ to obtain, after chromatography, 841 mg (55%) of 8cas a yellow oil. ¹H NMR (CDCl₃) δ 7.17 (t, 1H), 6.67 (d, 1H), 6.43. (d,1H), 4.37 (bm, 1H), 3.84, (m, 1H), 3.79 (s, 3H), 3.77 (bd, 1H), 3.33 (m,1H), 3.18 (bm, 2H), 1.48 (s, 9H), 1.01 (d, 3H). ESIMS: m/z 425 (M+Na⁺,100).

(Z)-1-tert-Butoxycarbonyl-4-(3-methoxyphenyl)-3,5-dimethylpiperazine(8d). General procedure b. was employed using 588 mg (2.74 mmol) ofBoc-piperazine 7d to obtain, after chromatography, 407 mg (46%) of 8d asa yellow oil. ¹H NMR (CDCl₃) δ 7.20 (t, 1H), 6.69 (m, 3H), 4.15 (m,0.7H), 3.89 (bm, 1.3H), 3.79 (s, 3H), 3.06 (m, 2H), 2.88 (m, 2H), 1.48(d, 9H), 1.20 (d, 2.1H), 0.81 (d, 3.1H). ESIMS: m/z 321 (M+H⁺, 50).

(2S,5S)-1-tert-Butoxycarbonyl-4-(3-methoxyphenyl)-2,5-dimethylpiperazine(8e). General procedure b. was employed using 433 mg (2.02 mmol) ofBoc-piperazine 7e to obtain, after chromatography, 397 mg (65%) of 8e asa yellow oil. ¹H NMR (CDCl₃) δ 7.17 (t, 1H), 6.52 (d, 1H), 6.47-6.45 (m,1H), 4.15 (q, 1H), 4.03-3.98 (m, 1H), 3.41 (q, 1H), 3.30 (dd, 1H),2.97-2.90 (dd, 1H), 2.84 (dd, 1H), 1.45 (s, 9H), 1.32 (d, 3H), 1.04 (d,3H). ESIMS: m/z 321 (M+H⁺, 50).

(2S,5R)-1-tert-Butoxycarbonyl-4-(3-methoxyphenyl)-2,5-dimethylpiperazine(16). General procedure a. was employed using 1.04 g (3.79 mmol) ofBoc-piperazine 15 to obtain, after chromatography, 288 mg (24%) of 16 asa yellow oil. ¹H NMR (CDCl₃) δ 7.12 (t, 1H), 6.46 (d, 1H), 6.37 (s, 1H),6.35 (d, 1H), 4.39 (b, 1H), 3.94 (bm, 1H), 3.79 (s, 3H), 3.78 (m, 1H),3.40 (dd, 1H), 3.25 (dd, 1H), 3.11 (d, 1H), 1.48 (s, 9H), 1.25 (d, 3H),1.03 (d, 3H). ESIMS: m/z 221 (M-Boc+H⁺, 95), 321 (M+H⁺, 20).

(2R,5S)-1-Allyl-4-(3-methoxyphenyl)-2,5-dimethylpiperazine (11). Generalprocedure a. was employed using 1.00 g (6.48 mmol) of allyl-piperazine10⁵ to obtain, after chromatography, 715 mg (55% yield) of 11 as ayellow oil. ¹H NMR (CDCl₃) δ 7.19 (t, 1H), 6.67 (dd, 1H), 6.62 (m, 1H),6.56 (dd, 1H), 5.91 (m, 1H), 5.27-5.17 (m, 2H), 3.79 (s, 3H), 3.45-3.26(m, 2H), 3.13 (dd, 1H), 3.00-2.89 (m, 2H), 2.82-2.64 (m, 2H), 2.21 (dd,1H), 1.06 (d, 3H), 0.98 (d, 3H). ESIMS: m/z 261 (M+H⁺, 100).

3-Piperazine-phenol Dihydrobromide (9a). General procedure d. wasemployed using 1.39 of 8a and 20 mL of conc. HBr. Recrystallization fromMeOH gave 1.05 (65%) of 9a as pink crystals: mp>220° C. ¹H NMR (d₆-DMSO)δ 8.75 (bs, 2H), 7.29 (bs, 2H), 7.16 (t, 1H), 6.55 (d, 1H), 6.51 (s,1H), 5.45 (d, 1H), 3.36 (m, 2H), 3.22 (m, 4H), 2.50 (m, 2H). ESIMS: m/z179 (M+H⁺, 100).

(S)-3-(2-Methylpiperazin-1-yl)phenol (9b) Dihydrobromide. Generalprocedure c. was employed using 714 mg (2.44 mmol) of 8b affording a tansolid that was triturated under cold MeOH and collected by filtration,624 mg (76%): mp>220° C. This compound had identical spectralinformation as 9c (see below).

(R)-3-(2-Methylpiperazin-1-yl)phenol (9c) Dihydrobromide. Generalprocedure c. was employed using 780 mg (2.54 mmol) of 8c affording a tansolid that was triturated under cold MeOH and collected by filtration,685 mg (76%): mp>220° C. ¹H NMR (CD₃OD) δ 7.33 (q, 1H, ArH), 6.97 (d,1H, ArH), 6.94 (s, 1H, ArH), 6.80 (d, 1H, ArH), 4.15 (m, 1H, NCH), 3.76(m, 1H, NCH), 3.71 (bd, 2H, NCH), 3.49 (dd, 1H, NCH), 1.18 (d, 3H, CH₃).ESIMS: m/z 193 (M+H⁺; 100).

(Z)-3-(2,6-Dimethylpiperazin-1-yl)phenol (9d). General procedure d. wasemployed using 407 mg (1.27 mmol) of 8d and 10 mL of conc. HBr. Thedihydrobromide salt was dissolved in MeOH, stirred over 200 mg of NaHCO₃for 10 min, and filtered. The solution was concentrated under reducedpressure and subjected to column chromatography on silica gel elutingwith CMA80 to afford 180 mg (65%) of 9d as a brown solid: mp>220° C. ¹HNMR (CDCl₃) δ 7.15 (t, 1H), 6.68 (m, 2H), 3.14 (m, 4H), 2.71 (dd, 2H,J=12 Hz), 0.80 (d, 3H). ESIMS: m/z 207 (M+H⁺, 100).

(2S,5S)-3-(2,5-Dimethylpiperazin-1-yl)phenol (9e). General procedure d.was employed using 397 mg (1.80 mmol) of 8e and 10 mL of conc. HBr. Thedihydrobromide salt was dissolved in MeOH, stirred over 200 mg of NaHCO₃for 10 min and then filtered. The solution was concentrated underreduced pressure and subjected to silica-gel column chromatographyeluting with CMA80-CH₂Cl₂ (1:1) to afford 522 mg (29%) of 9e as a greysolid: mp>220° C. ¹H NMR (CDCl₃) δ 7.10 (q, 1H), 6.52 (m, 1H), 6.45 (s,1H), 6.41 (m, 1H), 4.23 (m, 2H), 3.89-3.39 (m, 4H), 3.03 (dd, 2H), 1.45(d, 3H), 1.15 (d, 3H). ESIMS: m/z 207 (M+H⁺, 100).

3-[(2S,5R)-2,5-Dimethylpiperazin-1-yl]phenol (17) Dihydrobromide.General procedure c. was employed using 288 mg (0.90 mmol) of 16affording a crimson-colored residue that was pure by NMR (100%). ¹H NMR(CD₃OD) δ 7.44 (t, 1H), 7.23 (m, 2H), 6.97 (m, 1H), 4.39 (m, 1H), 4.22(m, 1H), 3.97-3.82 (m, 2H), 3.71 (m, 1H), 3.29 (m, 1H), 1.48 (d, 3H),1.25 (d, 3H). ESIMS: m/z 207 (M+H⁺, 100).

3-[(2R,5S)-2,5-Dimethylpiperazin-1-yl]phenol (13) In a round-bottomflask, 715 mg (2.74 mmol) of 12 was dissolved in 10 mL CH₃COOH and 5 mLof H₂O. To this mixture was added 50 mg of 10% Pd on carbon, and thesuspension was heated and stirred at reflux for 12 h. The mixture wascooled, filtered, and the solvents evaporated under reduced pressure. Tothe residue was added 20 mL of conc. NaHCO₃, and this mixture wasextracted thoroughly with EtOAc. The pooled organic extracts were washedonce with brine, dried over MgSO₄, and the solvents removed underreduced pressure to yield 605 mg of an orange oil that was pure(2R,5S)-1-(3-methoxyphenyl)-2,5-dimethylpiperazinium acetate by NMR. ¹HNMR (CDCl₃) δ 7.21 (t, 1H), 6.73 (dd, 1H), 6.62 (m, 1H), 6.67 (m, 1H),6.63 (m, 1H), 3.79 (s, 3H), 3.12-2.90 (m, 4H), 2.70 (dd, 1H), 2.46 (dd,1H), 1.07 (d, 3H), 0.93 (d, 3H). ESIMS: m/z 221 (M+H⁺, 100). Generalprocedure c. was employed using 363 mg (1.65 mmol) of this oil affordinga residue that was dissolved in 5 mL of MeOH and stirred over excessNaHCO₃. The mixture was filtered, and the solvents subjected to rotaryevaporation to afford a residue that was purified by chromatographyaffording 215 mg of 13 as a white solid (63% yield). Spectralinformation for this compound was found to be identical to 17.

3-(4-Phenylpropylpiperazin-1-yl)phenol (5a) Dihydrochloride. Generalprocedure e. was employed with 250 mg (0.735 mmol) of 9a. The crudeproduct was subjected to flash-column chromatography on silica geleluting with CMA80-CH₂Cl₂ (1:1). The freebase thus recovered wasconverted to the dihydrochloride salt by dissolving in 2 mL of a 2 M HClsolution in EtOH and removing the solvents under reduced pressure. Thesolids were suspended in EtOAc and collected by filtration to yield 55mg (20%) of 5a.2HCl as a tan powder: mp 194-201° C. (dec). ¹H NMR(CD₃OD) δ 7.33-7.21 (m, 5H), 7.09 (t, 1H), 6.52-6.38 (m, 3H), 3.81-3.76(bd, 2H), 3.67-3.63 (bd, 2H), 3.29-3.18 (m, 4H), 3.09-3.00 (bt, 2H),2.75 (t, 2H), 2.13 (m, 2H). ESIMS: m/z 297 (M+H⁺, 100). Anal. calcd forC₁₉H₂₆Cl₂N₂O: C, 61.79; H, 7.10; N, 7.55. Found: C, 61.72; H, 7.10; N,7.38.

(S)-3-(2-Methyl-4-phenylpropylpiperazin-1-yl)phenol (5b)Dihydrochloride. General procedure e. was employed using 247 mg (0.886mmol) of 9b. The dihydrochloride salt was made by dissolving the crudeproduct in 5 mL of a 2 M solution of HCl in EtOH and removing thesolvents under reduced pressure. This salt was recrystallized fromEtOH-EtOAc to yield 126 mg (37%) of 5b.2HCl as a white powder: mp>220°C. [α]=+2.17 (c 0.46, CH₃OH). The spectral information gathered for thiscompound were identical as those obtained for 5c (see below). Anal.calcd for C₂₀H₂₈Cl₂N₂O: C, 62.66; H, 7.36; N, 7.31. Found: C, 62.45; H,7.53; N, 7.29.

(R)-3-(2-Methyl-4-phenylpropylpiperazin-1-yl)phenol (5c)Dihydrochloride. General procedure e. was employed using 175 mg (0.886mmol) of 9c. The dihydrochloride salt was made by dissolving the productin 5 mL of a 2 M solution of HCl in EtOH and removing the solvents underreduced pressure. This salt was recrystallized from EtOH-EtOAc to yield55 mg (19%) of 5c.HCl as a white powder: mp>220° C.; [α] −2.17 (c 0.46,CH₃OH). ¹H NMR (CD₃OD) δ 7.40-7.27 (m, 9H), 3.95-3.70 (b, 2H), 3.70-3.50(b, 2H), 3.33 (m, 2H), 3.30 (m, 3H), 2.78 (t, 2H), 1.17 (d, 3H). ESIMS:m/z 311 (M+H⁺, 100). Anal. calcd for C₂₀H₂₈Cl₂N₂O: C, 62.66; H, 7.36; N,7.31. Found: C, 62.15; H, 7.36; N, 7.02.

(Z)-3-(2,6-Dimethyl-4-(3-phenylpropyl)piperazin-1-yl)phenol (5d)Dihydrochloride. General procedure e. was employed using 65 mg (0.315mmol) of 9d. The crude product was subjected to preparative TLC elutingwith CMA80-CH₂Cl₂ (1:1) which afforded 20 mg (20%) of 5d as anamber-colored residue. The 5d.2HCl was prepared by dissolving thismaterial in 5 mL of 2 M HCl in EtOH and removing the solvents underreduced pressure: mp 210-212° C. ¹H NMR (freebase in CDCl₃) δ 7.30-7.18(m, 4H), 7.13 (t, 1H), 6.67 (d, 1H), 6.66 (s, 1H), 6.59 (dd, 1H), 3.19(m, 2H), 2.81 (dd, 2H), 2.66 (t, 2H, J=9 Hz), 2.41 (dd, 2H), 2.08 (dd,2H, J=9 Hz), 1.88 (m, 3H), 0.81 (d, 6H, J=6 Hz). ESIMS: m/z 325 (M+H⁺,100). Anal. calcd for C₂₁H₃₀Cl₂N₂O.H₂O: C, 60.72; H, 7.76; N, 6.74.Found: C, 61.10; H, 7.80; N, 6.63.

3-[(2S,5S)-2,5-Dimethyl-4-(3-phenylpropyl)piperazin-1-yl]phenol (5e)Dihydrochloride. General procedure e. was employed using 83 mg (0.225mmol) of 9e. The crude product was subjected flash column chromatographyon silica gel eluting with CMA80-CH₂Cl₂ (1:1) which afforded anamber-colored residue. The dihydrochloride was prepared by dissolvingthis residue in 5 mL of 2 M HCl in EtOH and removing the solvents underreduced pressure. The residue was dissolved in 1 mL of MeOH, and thewhite crystals of 5e.2HCl were collected by filtration to afford 8 mg(9%): mp>220° C. (dec). ¹H NMR (freebase in CDCl₃) δ 7.30-7.18 (m, 4H),7.13 (t, 1H), 6.67 (d, 1H), 6.66 (s, 1H), 6.59 (dd, 1H), 3.19 (m, 2H),2.81 (dd, 2H), 2.66 (t, 2H, J=9 Hz), 2.41 (dd, 2H), 2.08 (dd, 2H, J=9Hz), 1.88 (m, 3H), 0.81 (d, 6H, J=6 Hz). ESIMS: m/z 325 (M+H⁺, 100).Anal. calcd for C₂₁H₃₀Cl₂N₂O: C, 60.72; H, 7.76; N, 6.74. Found: C,61.01; H, 7.70; N, 6.80.

(S)-3-(2,4-Dimethylpiperazin-1-yl)phenol (5e) Dihydrochloride. At roomtemperature and under an atmosphere of H₂ were stirred 109 mg (0.567mmol) of the piperazine 9b, 0.5 mL of Raney nickel slurry, andformaldehyde (0.5 mL of 37% in H₂O) in EtOH for 8 h in 15 mL of EtOH.The suspension was filtered and the solvents evaporated to yield a cruderesidue that was separated by silica gel column chromatography elutingwith CMA80-CH₂Cl₂ (1:1). The fractions containing the product wereremoved of solvent by rotary evaporation, acidified with a 2 M HClsolution in EtOH, and crystallized by addition of Et₂O and cooling togive 5f.2HCl: mp 179-183° C.; [α]_(D)+4.4° (c 0.18, MeOH). ¹H NMR(freebase in CDCl₃) δ 7.09 (t, 1H), 6.50 (dd, 1H), 6.41 (t, 1H), 6.34(dd, 1H), 3.75 (m, 1H), 3.15 (m, 1H), 2.76 (m, 1H), 2.55 (m, 2H), 2.36(m, 1H), 2.32 (s, 3H), 1.06 (d, 3H). ESIMS: m/z 207 (M+1, 100). Anal.calcd for C₁₂H₂₀Cl₂N₂O: C, 51.62; H, 7.22; N, 10.03. Found: C, 51.88; H,7.51; N, 9.89.

3-((2S,5R)-2,5-Dimethyl-4-(3-phenylpropyl)piperazin-1-yl)phenol (5g)Dihydrochloride. General procedure e. was employed using 175 mg (0.475mmol) of 17. The dihydrochloride salt was made by dissolving the crudeproduct in 5 mL of a 2 M solution of HCl in EtOH, and removing thesolvents under reduced pressure. The salt was triturated underEtOH-iPrOH, collected by filtration, and dried under vacuum to afford 88mg (47%) of pure 5g.HCl as a white powder: mp 199° C. (dec); [α]²⁵ _(D)−9.47 (c 0.57, MeOH). ¹H NMR (CD₃OD) δ 7.35-7.22 (m, 6H), 7.00-6.75 (m,3H), 4.00-3.78 (m, 3H), 3.65-3.29 (m, 4H), 3.20 (dt, 1H), 2.80 (m, 2H),2.15 (m, 1H), 1.38 (d, 3H), 1.11 (d, 3H). ESIMS: m/z 325 (M+H⁺, 100).Anal. calcd for C₂₁H₃₀Cl₂N₂O: C, 63.47; H, 7.61; N, 7.05. Found: C,63.47; H, 7.67; N, 6.89.

3-((2R,5S)-2,5-Dimethyl-4-(3-phenylpropyl)piperazin-1-yl)phenol (5h)Dihydrochloride. General procedure e. was employed using 47 mg (0.228mmol) of 13. The dihydrochloride salt was made by dissolving the crudeproduct in 5 mL of a 2 M solution of HCl in EtOH, and removing thesolvents under reduced pressure. The crude salt was triturated underEtOH-iPrOH, collected by filtration and dried under vacuum to afford 14mg (15%) of pure 5h.2HCl as a white powder with identical melting point(199° C. dec) and spectra as those reported for 5g.2HCl: [α]²⁵ _(D) +9.5(c 0.55, MeOH). Anal. calcd for C₂₁H₃₀Cl₂N₂O: C, 63.47; H, 7.61; N,7.05. Found: C, 63.31; H, 7.51; N, 7.29.

3-{(2S)-4-[(2S)-2-Amino-3-methylbutyl]-2-methylpiperazin-1-yl}phenol(5i) Trihydrochloride. In a round-bottom flask, 570 mg (2.49 mmol) of 9bwere dissolved in dry THF (30 mL) along with 542 mg (2.49 mmol) ofN-Boc-L-valine. The solution was cooled to 0° C. in an ice-bath and 1.38mL (9.97 mmol) of Et₃N were added followed by 1.10 g (2.49 mmol) of BOP.The flask was removed from the ice bath and the reaction was stirred for2 h. The solution was then dumped on concentrated aqueous NaHCO₃solution, and the mixture extracted three times with 15 mL of EtOAc. Thepooled organic extracts were washed with brine, dried (MgSO₄), filtered,and the solution concentrated to leave a residue that was purified byflash column chromatography on silica gel to yield 415 mg (42%) of theintermediate amide. This amide was dissolved in 20 mL of THF, and 3.18mL (3.18 mmol) of a 1 M solution of BH₃THF were added. The solution wasstirred at reflux overnight cooled to RT and quenched with 5 mL of H₂O.Into this solution was added 10 mL of conc. HCl, and the mixture wasstirred for 1 hr and 20 mL of water were added. Solid NaHCO₃ was thenadded to adjust the solution to a pH of 8. The mixture was extractedthree times with 5 mL of CH₂Cl₂, washed with brine, and dried (MgSO₄).Rotary evaporation of the solution afforded a residue that was purifiedby flash-column chromatography on silica gel eluting withCMA80-hexanes-EtOAc (6:2:1) to yield 241 mg (82%) of 5i as a whitesolid. An analytic sample of the trihydrochloride salt 5i.3HCl wasprepared by recrystallization from EtOAc-hexanes: mp 210-212° C.; [α]²⁵_(D) +48.8° (c 0.1, MeOH). ¹H NMR (CD₃OD) δ 7.46-7.40 (t, 1H), 7.16 (m,2H), 6.98 (d, 1H), 4.14 (m, 1H), 3.96 (m, 1H), 3.65 (m, 1H), 3.30 cm,3H), 2.95 (m, 3H), 2.00 (m, 1H) 1.23-1.03 (m, 9H). ESIMS: m/z 278 (M+H⁺,100). Anal. calcd for C₁₆H₃₀Cl₃N₃O.H₂O: C, 47.47; C, 7.97; N, 10.38.Found: C, 47.02; H, 7.96; N, 10.03.

(3R)-7-Hydroxy-N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(5j) Trihydrochloride. In a round-bottom flask, 120 mg (0.432 mmol) of5i and 133 mg (0.454 mmol) of 7-OH-Boc-D-Tic were dissolved in dry THF(15 mL), and the solution was cooled to 0° C. Into this solution 0.06 mLof Et₃N were added followed by 201 mg (0.454 mmol) of BOP. The solutionwas warmed up to room temperature, stirred for 3 h, and then added to anice-cold concentrated NaHCO₃ solution. The mixture was extracted threetimes with 5 mL of EtOAc. The pooled organic extracts were washed oncewith conc. NaHCO₃ solution, once with brine, and dried (MgSO₄). Thefiltrates were concentrated under reduced pressure to yield a residuethat was dissolved in 5 mL of CH₂Cl₂ and 3 mL of CF₃CO₂H and stirredovernight. The solvents were reduced under reduced pressure to yield aresidue, which was stirred with 10 mL of conc. NaHCO₃ solution and 10 mLof EtOAc. The layers were separated, and the aqueous layer was extractedthree times with 3 mL of EtOAc. The pooled organic extracts were washedonce with brine, dried (MgSO₄), and filtered. The filtrates wereconcentrated under reduced pressure to yield a residue that was purifiedby flash-column chromatography on silica gel eluting withCMA80-EtOAc-hexanes (2:1:1) to yield a residue that was dissolved in 3mL of a 2 M solution of HCl in EtOH. The solvent was removed underreduced pressure to leave a solid that was triturated under MeOH to give61 mg (31%) of 5j.3HCl: mp>220° C. (dec); [α] +67.6 (c 0.21, CH₃OH). NMR(CD₃OD) δ 8.75 (d, 1H), 7.38 (b, 1H), 7.10 (b+d, 3H), 6.92 (b, 1H), 6.76(dd, 1H), 6.67 (d, 1H), 4.44-4.33 (m, 6H), 3.91-3.67 (m, 3H), 3.67-3.50(m, 2H), 3.50-3.35 (m, 2H), 3.31-3.21 (m, 1H), 2.81 (dd, 1H) 1.92 (m,1H), 1.18 (b, 3H), 1.05 (t, 6H). ESIMS: m/z 453 (M+H⁺, 100). Anal. calcdfor C₂₆H₃₉Cl₃N₄O₃.3H₂O: C, 50.69; H, 7.36; N, 9.09. Found: C, 50.66; H,7.09; H, 8.95.

TABLE 1 Comparison of Inhibition of Agonist Stimulated [³⁵S]GTPγSBinding in Cloned Human μ, δ, and κ-Opioid Receptors for Compounds A

B

μ, DAMGO δ, DPDPE κ, U69,593 compd Structure R₁ R₂ R₃ R₄ R₅ K_(e) (nM)K_(e) (nM) k_(e) (nM) μ/κ δ/κ norBNI 26 ± 7  29 ± 8  0.05 ± 0.02  52∪580 JDTic A ^(a) 25.1 ± 3.5  76.4 ± 2.7  0.02 ± 0.01 1255 3830 2b A CH₃29 ± 3  680 ± 240 155 ± 24  2c A C₆H₅(CH₂)₃ 0.10 ± 0.02 0.90 ± 0.3  0.88± 0.20 5a B H H H H C₆H₅(CH₂)₃ 8.5 ± 1.4 34 ± 6  15 ± 3  5b B H (S)CH₃ HH C₆H₅(CH₂)₃ 0.88 ± 0.03 13.4 ± 4.2  4.09 ± 0.79 5c B H (R)CH₃ H HC₆H₅(CH₂)₃ 1.0 ± 0.2 7.0 ± 2   1.5 ± 0.4 5d B (Z)CH_(3,) CH₃ H HC₆H₅(CH₂)₃ 3 4300 3 5e B H (S)CH₃ H (S)CH₃ C₆H₅(CH₂)₃ —   7 ± 0.3 5f B H(S)CH₃ H H CH₃ 508 ± 26  NA 193 ± 19  5g B H (S)CH₃ H (R)CH₃ C₆H₅(CH₂)₃6.1 ± 1.7 55 ± 3  4.2 ± 0.8 5h B H (R)CH₃ H (S)CH₃ C₆H₅(CH₂)₃ 18 ± 4 179 ± 68  26 ± 7  5i B H (S)CH₃ H H CH₂CH[(CH₃)₂CH]NH₂ 2 55 10 5j B H(S)CH₃ H H a 22 ± 4  274 ± 48  2.7 ± 0.1

Additional Examples

A. Compound 12 and Intermediates:

(2R,5R)-1-tert-butoxycarbonyl-2,5-dimethylpiperazine (19). A solution of1.43 g (5.19 mmol) of (2R,5R)-2,5-dimethyl piperazine dihydrobromide 18¹was dissolved in 30 mL of MeOH along with 262 mg (2.59 mmol) of Et₃N.Into this solution was added 565 mg (2.59 mmol) of Boc₂O and thesolution was stirred overnight. The solution was subjected to rotaryevaporation and added 20 mL of CH₂Cl₂ and 20 ml of conc. NaHCO₃. Themixture was shaken thoroughly and the layers separated. The organiclayer was extracted twice with conc. NaHCO₃ and the organic layer driedover MgSO₄, filtered and the solvents removed. The residue was purifiedby silica-gel column chromatography eluting with 2:1 CMA80:CH₂Cl₂ toyield 497 mg (84%) of pure 19 as a clear oil. ¹H NMR (CDCl₃): δ4.28-4.02 (bd, 1H); 3.90-3.63 (bdd, 1H); 2.99-2.94 (dd, 1H); 2.81-2.75(d, 1H); 2.71-2.62 (m, 1H); 2.53-2.49 (d, 6H); 1.25 (d, 3H); 1.06 (d,3H). ESIMS: m/z 215 (M+H⁺, 100).

(2R,5R)-1-tert-butoxycarbonyl-4-(3-methoxyphenyl)-2,5-dimethylpiperazine(20). General procedure b. was employed using 546 mg (2.55 mmol) ofBoc-piperazine 19g to obtain, after chromatography, 515 mg (63%) of 20as a yellow oil. ¹H NMR (CDCl₃): δ 7.17 (t, 1H, J=9 Hz); 6.52 (d, 1H);6.47-6.45 (m, 1H); 4.15 (q, 1H, J=6 Hz); 4.03-3.98 (m, 1H); 3.41 (m,1H); 3.30 (dd, 1H, J_(a)=6 Hz, J_(b)=12 Hz); 2.97-2.90 (dd, 1H, J_(a)=6Hz J_(b)=12 Hz); 2.84 (dd, 1H J_(a)=12 Hz, J_(b)=3 Hz); 1.45 (s, 9H);1.32 (d, 3H, J=6 Hz); 1.04 (d, 3H, J=6 Hz). ESIMS: m/z 321 (M+H⁺, 50).

(2R,5R)-3-(2,5-dimethylpiperazin-1-yl)phenol (21). General procedure d.was employed using 515 mg (1.61 mmol) of 20 and 10 mL of conc. HBr. Thedihydrobromide salt was dissolved in MeOH, stirred over 200 mg of NaHCO₃for 10 minutes and then filtered. The solution was concentrated underreduced pressure and the crystallized from MeOH/Et₂O to yield 407 mg(69%) of 21e as a white solid: mp>220° C. ¹H NMR (CDCl₃): δ 7.10 (q,1H); 6.52 (m, 1H); 6.45 (s, 1H); 6.41 (m, 1H); 4.23 (m, 2H); 3.89-3.39(m, 4H); 3.03 (dd, 2H); 1.45 (d, 3H, J=6 Hz); 1.15 (d, 3H, J=6 Hz).ESIMS: m/z 207 (M+H⁺, 100).

3-[(2R,5R)-2,5-Dimethyl-4-(3-phenylpropyl)piperazin-1-yl]phenoldihydrochloride (22). General procedure f. was employed using 300 mg(0.225 mmol) of 21. The dihydrochloride was prepared by addition of a 2M HCl solution in EtOH and rotary evaporation. The crude HCl salt wasrecrystallized from EtOH/Et₂O to afford 260 mg (80%) of 22 as a whitecrystalline solid. MP>220° C. (dec). ¹H NMR (CD₃OD): δ 7.26-7.19 (m,4H); 7.07 (m, 1H); 6.62 (m, 1H); 6.45 (d, 1H, J=9 Hz); 6.37-6.33 (m,2H); 4.26 (m, 1H); 3.58-3.30 (m, 4H); 3.22-3.03 (m, 2H); 2.75 (t, 2H,J=5 Hz); 2.20-2.01 (m, 2H); 1.50 (d, 1H, J=6 Hz); 1.42 (d, 2H, J=6 Hz);1.14 (d, 2H, J=6 Hz); 0.97 (d, 1H, J=6 Hz). ESIMS: m/z 325 (M+H⁺, 100).α]_(D) ²⁵ −12.3° (c 1, MeOH).

B. Process for the Preparation of Alkylpiperazines:

2-Ethyl-piperazine (25). The cyclic glycine-(2-ethyl-glycine)dipeptide23^(2, 3) (0.11 g, 7.81 mmol) was suspended in 20 mL of dry THF and 31.2mL of a 1 M solution of BH₃.THF were added. This mixture was stirred atreflux overnight cooled, and quenched with 10 mL of MeOH. Into thissolution, 5 mL of conc. HBr were added, and the solvents were removed byrotary evaporation. The residue was recrystallized from MeOH/Et₂O giving1.08 g of the product as a white solid. The freebase was made bydissolving the salt in MeOH, stirring over NaHCO₃, adding EtO₂,filtering and removing the solvents to yield a clear oil, ¹H NMR(CD₃OD): δ 30.91 (t, J=7 Hz, 3 H), 1.20-1.30 (m, 2 H), 2.30-3.30 (m, 7H). ESIMS: m/z 115 (M+H⁺, 100).

1-tert-butoxycarbonyl-3-ethyl-piperazine (26). A solution of 1.00 g(3.62 mmol) of 2-ethylpiperazine dihydrobromide 25 in 10 mL of MeOH. wascooled to 0° C. Into this flask was added 0.50 mL (3.62 mmol) of Et₃Nfollowed by a solution of 790 mg of Boc₂O in 10 mL added dropwise over 4h. The mixture was stirred for 12 h and then subjected to rotaryevaporation. The remaining residue was purified by silica-gel columnchromatography eluting with 1:1 CMA80:CH₂Cl₂ affording 700 mg of 26 as ayellow oil. ¹H NMR (CDCl₃): δ 3.95 (bs, 2H); 2.97 (d, 1H, J=9 Hz); 2.77(m, 2H); 2.48 (m, 2H); 1.46 (s, 9H); 1.40 (m, 2H); 0.95 (t, 3H, J=6 Hz)ESIMS: m/z 215 (M+H⁺, 75); 115 (M-Boc+H⁺, 100).

1-tert-butoxycarbonyl-3-ethyl-4-(3-methoxyphenyl)piperazine (27).General procedure b. was employed using 0.30 g (5.35 mmol) of 26 toobtain, after chromatography, 0.20 g (44%) of 27 as a clear oil. ¹H NMR(CDCl₃): δ 7.17 (t, 1H, J=9 Hz); 6.47 (dd, 1H, J_(a)=3 Hz, J_(b)=9 Hz);6.38 (s, 1H); 4.05 (s, 2H); 3.79 (s, 3H); 3.55 (m, 1H); 3.24-3.06 (m,4H); 1.48 (m, 11H); 0.92 (t, 3H, J=9 Hz). ESIMS: m/z 321 (M+H⁺, 100).

3-(2-ethylpiperazin-1-yl)phenol dihydrobromide (28). General procedurec. was employed using 200 mg (2.54 mmol) of 10c. The crudedihydrobromide was dissolved in 1 mL of MeOH stirred over NaHCO₃ andpurified by silica-gel column chromatography eluting with 2:1CMA80:CH₂Cl₂ to afford 105 mg of product was a clear oil. ¹H NMR(CD₃OD): δ 7.08 (t, 1H, J=9 Hz); 6.43 (d, 1H); 6.34 (s, 1H); 6.27 (d,1H, J=9 Hz); 3.47 (m, 1H); 3.18 (m, 1H); 3.07-2.90 (m, 5H); 1.65 (m,1H); 1.47 (m, 1H); 0.86 (t, 3H, J=6 Hz). ESIMS: m/z 207 (M+H⁺, 100).

3-[2-ethyl-4-(3-phenylpropyl)piperazin-1-yl]phenol dihydrochloride (29).General procedure f. was employed using 100 mg (0.485 mmol) 10x toobtain, after salt formation, 55 mg of the dihydrochloride: mp 161-166°C. ¹H NMR (CD₃OD): δ 7.35-7.15 (m, 7H); 7.12 (bs, 1H); 6.91 (bs, 1H);4.11-3.50 (m, 5H); 2.77 (t, 2H, J=6 Hz), 2.20 (m, 2H); 1.63 (m, 2H),0.90 (t, 3H, J=6 Hz). ESIMS: m/z 325 (M+H⁺, 100).

C. Process for the synthesis of N-alkylamino1-(3-hydroxyophenyl)-2-(S)-methylpiperazines

Synthesis of N-substituted (S)-3-(2-methylpiperazin-1-yl)phenols 30 and31

Compounds bearing 4-N-substituents were synthesized in a manner similarto compounds in the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinesreported by Thomas et al⁴. (S)-3-(2-methylpiperazin-1-yl)phenoldihydrobromide was acylated using a series of amino acids and thepeptide linking reagent HBTU. Without purification, the resulting amideswere reduced with BH₃.THF to yield the N-substituted compounds 14.

General Procedure:Reductive Alkylation Using N-Boc-Protected Amino Acids

(S)-3-(2-methylpiperazin-1-yl)phenol dihydrobromide (100 mg, 0.282 mmol)and the N-Boc-protected amino acid (0.311 mmol) were dissolved in 1.5 mLof CH₃CN and 0.12 mL (0.847 mmol) of Et₃N. Into this mixture was addedall at once, a solution of HBTU (118 mg, 0.311 mmol) in 2 mL of CH₃CN.The reaction was stirred overnight. To the reaction mixture were added0.5 mL of CH₂Cl₂ followed by 2 mL of a saturated aqueous solution ofNaHCO₃. The mixture was shake, and the organic layer separated andwashed again with 2 mL conc. NaHCO₃. The solvents were dried overNa₂SO₄, filtered and the solution was rotary evaporated and placed undervacuum to yield a brown foam. This material was dissolved in 2 mL of dryTHF and 2 mL of a 1 M solution of BH₃ THF and the solution stirred for24 h. Carefully, 0.5 mL of conc. HCl were added and the mixture wasstirred for 4 h, and subjected to rotary evaporation. The residue waspurified by crystallization or silica-gel column chromatography.

3-{(2S)-4-[(2-amino-ethyl]-2-methylpiperazin-1-yl}phenol (31a) Thegeneral procedure was employed using Boc-Glycine (54 mg, 0.311 mmol).The residue was crystallized from MeOH/Et₂O to yield 25 mg of theproduct as a tan solid: mp>230° C. ¹H NMR (CD₃OD): δ 7.40 (t, 1H, J=6Hz); 7.10 (m, 2H); 6.93 (bd, 1H); 4.15 (m, 1H); 3.98-3.88 (bt, 1H);3.75-3.68 (m, 1H); 3.60-3.50 (bd, 1H); 3.50-3.39 (bd, 1H); 3.15-3.01 (m,2H); 1.36 (d, 3H, J=6 Hz). ESIMS: m/z 236 (M+H⁺, 100).

3-{(2S)-4-[(2R)-2-amino-propyl]-2-methylpiperazin-1-yl}phenol (31b). Thegeneral procedure was employed using Boc-D-Alanine (59 mg, 0.311 mmol).The residue was crystallized from MeOH/Et₂O to yield 55 mg of theproduct as a white solid: mp 210-215° C. ¹H NMR (CD₃OD): δ 7.44 (t, 1H,J=6 Hz); 7.16 (m, 2H); 6.98 (m, 1H); 4.16 (bm, 1H); 3.99 (bt, 1H); 3.67(m, 1H); 3.50-3.30 (m, 2H); 3.12-2.85 (bm, 3H); 1.36 (d, 3H, J=6 Hz);1.17 (d, 3H, J=6 Hz). ESIMS: m/z 250 (M+H⁺, 100).

-   1. Tanatani, A.; Mio, M. J.; Moore, J. S., Chain Length-Dependent    Affinity of Helical Foldamers for a Rodlike Guest. Journal of the    American Chemical Society 2001, 123, (8), 1792-1793.-   2. Ognyanov, V. I.; Balan, C.; Bannon, A. W.; Bo, Y.; Dominguez, C.;    Fotsch, C.; Gore, V. K.; Klionsky, L.; Ma, V. V.; Qian, Y.-X.;    Tamir, R.; Wang, X.; Xi, N.; Xu, S.; Zhu, D.; Gavva, N. R.;    Treanor, J. J. S.; Norman, M. H., Design of Potent, Orally Available    Antagonists of the Transient Receptor Potential Vanilloid 1.    Structureâ^' Activity Relationships of    2-Piperazin-1-yl-1H-benzimidazoles. Journal of Medicinal Chemistry    2006, 49, (12), 3719-3742.-   3. Smith, G. G.; Evans, R. C.; Baum, R., Neighboring residue    effects: evidence for intramolecular assistance to racemization or    epimerization of dipeptide residues. Journal of the American    Chemical Society 1986, 108, (23), 7327-7332.-   4. Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman, R. B.;    Mascarella, S. W.; Xu, H.; Parana, J. S.; Dersch, C. M.;    McCullough, K. B.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F.    I., Identification of an Opioid Kappa Receptor Subtype-Selective    N-Substituent for    (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine. Journal of    Medicinal Chemistry 1998, 41, (26), 5188-5197.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

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The invention claimed is:
 1. A method of antagonizing opioid receptors,comprising administering to a subject in need thereof an effectiveamount of an opioid receptor antagonist represented by the formula (I):

wherein R is OH, OC₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl substituted by one or more Y₁ groups, CH₂-arylwherein the aryl group is substituted by one or more Y₁ groups, OCOC₁₋₈alkyl, COC₁₋₈ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₈ alkyl, or NHCO₂C₁₋₈alkyl; Y₃ is hydrogen, Br, Cl, F, CF₃ NO₂, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂; R₁, R₂, R₃ andR₄ are each, independently, one of the following structures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to form acyclo alkyl group or a bridged heterocyclic ring, wherein at least oneof R₁, R₂, R₃ and R₄ is other than hydrogen; each Y₁ is, independently,hydrogen, OH, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, or CONR₁₃R₁₄, or two adjacent Y₁ groups forma —O—CH₂—O— or —O—CH₂CH₂—O— group; each Y₂ is, independently, hydrogen,CF₃, CO₂R₉, C₁₋₈ alkyl, NR₁₀R₁₁,NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, CH₂OH,CH₂OR₈, COCH₂R₉,

each n is, independently, 0, 1, 2 or 3; each o is, independently, 0, 1,2 or 3; each R₈, R₉, R₁₀, R₁₁, R₁₂,R₁₃ and R₁₄ is, independently,hydrogen, C₁₋₈ alkyl, CH₂-aryl wherein the aryl group is substituted byone or more substituents OH, Br, Cl, F, CN, CF₃, NO₂ N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; each Y₂′ is, independently, hydrogen, CF₃, or C₁₋₆alkyl; R₅ is

 wherein n is 3,

 wherein n is 0, 1, 2 or 3,

 wherein n is 2 or 3,

 wherein n is 1, 2 or 3,

 wherein n is 0, 1, 2 or 3, —CH₂CH₂—X—R₆, or

R₆ is C₂₋₈ alkenyl, C₁₋₄ alkyl substituted C₄₋₈ cycloalkyl, C₁₋₄ alkylsubstituted C₄₋₈ cycloalkenyl, or thiophene; X is a single bond, —C(O)—or —CH(OR₁₅)—; R₁₅ hydrogen, C₁₋₆ alkyl, —(CH₂)_(q)-phenyl or —C(O)—R₁₆;R₁₆ is C₁₋₄ alkyl or —(CH₂)_(q)-phenyl; each q is, independently, 1, 2or 3; R₁₇ is hydrogen, C₁₋₈ alkyl, CO₂C₁₋₈ alkylaryl substituted by oneor more Y₁ groups, CH₂-aryl substituted by one or more Y₁ groups, orCO₂C₁₋₈ alkyl; R₁₈ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈ alkynyl,CH₂CO₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl or CH₂-aryl substituted by one or moreY₁ groups; R₁₉, is a group selected from the group consisting ofstructures (a)-(p):

Q is NR₂₁, CH₂, O, S, SO, or SO₂; each Y₄ is, independently, Br, Cl, F,CN, CF₃, NO₂, N₃, OR₂₂, CO₂R₂₃, C₁₋₆ alkyl, NR₂₄R₂₅, NHCOR₂₆, NHCO₂R₂₇,CONR₂₈R₂₉, or CH₂(CH₂)_(n)Y₂, or two adjacent Y₄ groups form a —O—CH₂—O—or —O—CH₂CH₂—O— group; p is 0, 1, 2,or 3; R₂₀ is hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, CH₂OR₃₀, or CH₂-aryl substituted by one or more Y₁substituents; each R₂₁ is, independently, hydrogen, C₁₋₈ alkyl, CH₂-arylsubstituted by one or more Y₁ substituents, NR₃₁R₃₂, NHCOR₃₃, NHCO₂R₃₄,CONR₃₅R₃₆, CH₂(CH₂)_(n)Y_(2,)or C(═NH)NR₃₇R₃₈; R₃₀ is hydrogen C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkenyl, CH₂O₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl, orCH₂-aryl substituted by one or more Y₁ substituents; R₂₂, R₂₃, R₂₄, R₂₅,R₂₆, R₂₇, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇ and R₃₈ are,independently, hydrogen, C₁₋₈ alkyl, CH₂-aryl substituted by one or moresubstituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; Z is N or S, wherein when Z is S, there is no R₁₈; X₁is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl; X₂ is hydrogen,C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl; or X₁ and X₂ together form═O, ═S, or ═NH; or a pharmaceutically acceptable salt thereof.
 2. Themethod of claim 1, wherein R is OH, OC₁₋₃ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl substituted by one or moreY₁ groups, CH₂-aryl wherein the aryl group is substituted by one or moreY₁ groups, OCOC₁₋₄ alkyl, COC₁₋₄ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₄alkyl, or NHCO₂C₁₋₄ alkyl; and Y₃ is hydrogen, Br, Cl, F, CF₃, NO₂, OR₈,CO₂R₉, C₁₋₃ alkyl, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ orCH₂(CH₂)_(n),Y₂.
 3. The method of claim 1, wherein R is OH, OCH₃, orOCF₃; and Y₃ is hydrogen.
 4. The method of claim 1, wherein R₁, R₂, R₃and R₄ are each, independently, hydrogen, methyl or ethyl; and at leastone of R₁, R₂, R₃ and R₄ is other than hydrogen.
 5. The method of claim1, wherein R₁, R₂, R₃ and R₄ are each, independently, hydrogen ormethyl; and at least one of R₁, R₂, R₃ and R₄ is methyl.
 6. The methodof claim 1, wherein R is OH, OCH₃, or OCF₃; Y₃ is hydrogen; R₁ R₂, R₃and R₄ are each, independently, hydrogen, methyl or ethyl, wherein atleast one of R₁, R₂, R₃ and R₄ is other than hydrogen; and R₅ is—(CH₂)_(n)-phenyl, wherein n is
 3. 7. The method of claim 1, wherein R₅is


8. The method of claim 1, wherein the opioid receptor antagonist isrepresented by the formula:

or a pharmaceutically acceptable salt thereof.
 9. A method of treatingdrug addiction, drug abuse, depression, anxiety, schizophrenia, obesityand eating disorders, comprising administering to a subject in needthereof an effective amount of an opioid receptor antagonist representedby the formula (I):

wherein R is OH, OC₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈alkenyl,C₂₋₈ alkynyl, aryl substituted by one or more Y₁ groups, CH₂-arylwherein the aryl group is substituted by one or more Y₁ groups, OCOC₁₋₈alkyl, COC₁₋₈ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₈ alkyl, or NHCO₂C₁₋₈alkyl; Y₃ is hydrogen, Br, Cl, F, CF₃, NO₂, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂; R₁, R₂, R₃ andR₄ are each, independently, one of the following structures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to form acyclo alkyl group or a bridged heterocyclic ring, wherein at least oneof R₁, R₂, R₃ and R₄ is other than hydrogen; each Y₁ is, independently,hydrogen, OH, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, or CONR₁₃R₁₄, or two adjacent Y₁ groups forma —O—CH₂—O— or —O—CH₂CH₂—O— group; each Y₂ is, independently, hydrogen,CF₃, CO₂R₉, C₁₋₈ alkyl, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, CH₂OH,CH₂OR₈, COCH₂R₉,

each n is, independently, 0, 1, 2 or 3; each o is, independently, 0, 1,2 or 3; each R₈, R₉, R₁₀, R₁₁, R₁₂,R₁₃ and R₁₄ is, independently,hydrogen, C₁₋₈ alkyl, CH₂-aryl wherein the aryl group is substituted byone or more substituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; each Y₂′ is, independently, hydrogen, CF₃, or C₁₋₆alkyl; R₅ is

 wherein n is 3,

 wherein n is 0, 1, 2 or 3,

 wherein n is 2or 3,

 wherein n is 1, 2 or 3,

 wherein n is 0, 1, 2 or 3, —CH₂CH₂—X—R₆, or

R₆ is C₂₋₈alkenyl, C₁₋₄ alkyl substituted C₄₋₈cycloalkyl, C₁₋₄alkylsubstituted C₄₋₈ cycloalkenyl, or thiophene; X is a single bond, —C(O)—or —CH(OR₁₅)—; R₁₅ hydrogen, C₁₋₆ alkyl, —(CH₂)_(q)-phenyl or —C(O)—R₁₆;R₁₆ is C₁₋₄ alkyl or —(CH₂)_(q)-phenyl; each q is, independently, 1, 2or 3; R₁₇ is hydrogen, C₁₋₈ alkyl, CO₂C₁₋₈ alkylaryl substituted by oneor more Y₁ groups, CH₂-aryl substituted by one or more Y₁ groups, orCO₂C₁₋₈ alkyl; R₁₈ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈ alkynyl,CH₂CO₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl or CH₂-aryl substituted by one or moreY₁ groups; R₁₉ is a group selected from the group consisting ofstructures (a)-(p):

Q is NR₂₁, CH₂, O, S, SO, or SO₂; each Y₄ is, independently, Br, Cl, F,CN, CF₃, NO₂, N₃, OR₂₂, CO₂R₂₃, C₁₋₆ alkyl, NR₂₄R₂₅, NHCOR₂₆, NHCO₂R₂₇,CONR₂₈R₂₉, or CH₂(CH₂)_(n)Y₂, or two adjacent Y₄ groups form a —O—CH₂—O—or —O—CH₂CH₂—O— group; p is 0, 1, 2, or 3; R₂₀ is hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, CH₂OR₃₀, or CH₂-aryl substituted by one or more Y₁substituents; each R₂₁ is, independently, hydrogen, C₁₋₈ alkyl, CH₂-arylsubstituted by one or more Y₁ substituents, NR₃₁R₃₂, NHCOR₃₃, NHCO₂R₃₄,CONR₃₅R₃₆,CH₂(CH₂)_(n)Y₂,or C(═NH)NR₃₇R₃₈; R₃₀ is hydrogen C₁₋₈ alkyl,C₂₋₈ alkenyl, C,₂₋₈ alkenyl, CH₂O₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl, or CH₂-arylsubstituted by one or more Y₁ substituents; R₂₂, R₂₃, R₂₄ R₂₅, R₂₆, R₂₇,R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇ and R₃₈ are, independently,hydrogen, C₁₋₈ alkyl, CH₂-aryl substituted by one or more substituentsOH, Br, Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, or CH₂(CH₂)_(n)Y₂′; Z is Nor S wherein when Z is S, there is no R₁₈; X₁ is hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, or C₂₋₈ alkynyl; X₂ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,or C₂₋₈ alkynyl; or X₁ and X₂, together form ═O, ═S, or ═NH; or apharmaceutically acceptable salt thereof.
 10. The method of claim 9,wherein R is OH, OC₁₋₃ alkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkenyl,C₂₋₄ alkynyl, aryl substituted by one or more Y₁ groups, CH₂-arylwherein the aryl group is substituted by one or more Y₁ groups, OCOC₁₋₄,alkyl, COC₁₋₄ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₄ alkyl, or NHCO₂C₁₋₄alkyl; and Y₃ is hydrogen, Br, Cl, F, CF₃, NO₂, OR₈, CO₂R₉, C₁₋₃alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂.
 11. The methodof claim 9, wherein R is OH, OCH₃, or OCF₃; and Y₃ is hydrogen.
 12. Themethod of claim 9, wherein R₁, R₂, R₃ and R₄ are each, independently,hydrogen, methyl or ethyl; and at least one of R₁, R₂, R₃ and R₄ isother than hydrogen.
 13. The method of claim 9, wherein R₁, R₂, R₃ andR₄ are each, independently, hydrogen or methyl; and at least one of R₁,R₂, R₃ and R₄ is methyl.
 14. The method of claim 9, wherein R is OH,OCH₃, or OCF₃; Y₃ is hydrogen; R₁, R₂, R₃and R₄ are each, independently,hydrogen, methyl or ethyl, wherein at least one of R₁, R₂, R₃ and R₄ isother than hydrogen; and R₅ is —(CH₂)_(n)-phenyl, wherein n is
 3. 15.The method of claim 9, wherein R₅ is


16. The method of claim 9, wherein the opioid receptor antagonist isrepresented by the formula:

or a pharmaceutically acceptable salt thereof.
 17. A method of treatingalcohol addiction, nicotine addiction, cocaine addiction andmethamphetamine addiction, comprising administering to a subject in needthereof of an effective amount of an opioid receptor antagonistrepresented by the formula (I):

wherein R is OH, OC₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈alkenyl,C₂₋₈ alkynyl, aryl substituted by one or more Y₁ groups, CH₂-arylwherein the aryl group is substituted by one or more Y₁ groups, OCOC₁₋₈alkyl, COC₁₋₈ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₈ alkyl, or NHCO₂C₁₋₈alkyl; Y₃ is hydrogen, Br, Cl, F, CF₃, NO₂, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂; R₁, R₂, R₃ andR₄ are each, independently, one of the following structures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to form acyclo alkyl group or a bridged heterocyclic ring, wherein at least oneof R₁, R₂, R₃ and R₄ is other than hydrogen; each Y₁ is, independently,hydrogen, OH, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, or CONR₁₃R₁₄, or two adjacent Y₁ groups forma —O—CH₂—O— or —O—CH₂CH₂—O— group; each Y₂ is, independently, hydrogen,CF₃, CO₂R₉, C₁₋₈ alkyl,NR₁₀R₁₁,NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, CH₂OH,CH₂OR₈, COCH₂R₉,

each n is, independently, 0, 1, 2 or 3; each o is, independently, 0, 1,2 or 3; each R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ is, independently,hydrogen, C₁₋₈alkyl, CH₂-aryl wherein the aryl group is substituted byone or more substituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; each Y₂′ is, independently, hydrogen, CF₃, or C₁₋₆alkyl; R₅ is

 wherein n is 3,

 wherein n is 0, 1, 2 or 3,

 wherein n is 2 or 3,

 wherein n is 1, 2 or 3,

 wherein n is 0, 1, 2 or 3, —CH₂CH₂—X—R₆, or

R₆ is C₂₋₈alkenyl, C₁₋₄ alkyl substituted C₁₋₄ cycloalkyl, C₁₋₄alkylsubstituted C₄₋₈ cycloalkenyl, or thiophene; X is a single bond, —C(O)—or —CH(OR₁₅)—; R₁₅ hydrogen, C₁₋₆ alkyl, —(CH₂)_(q)-phenyl or —C(O)—R₁₆;R₁₆ is C₁₋₄ alkyl or —(CH₂)_(q)-phenyl; each q is, independently, 1, 2or 3; R₁₇ is hydrogen, C₁₋₈ alkyl, CO₂C₁₋₈ alkylaryl substituted by oneor more Y₁ groups, CH₂-aryl substituted by one or more Y₁ groups, orCO₂C₁₋₈ alkyl; R₁₈ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈alkynyl,CH₂CO₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl or CH₂-aryl substituted by one or moreY₁ groups; R₁₉, is a group selected from the group consisting ofstructures (a)-(p):

Q is NR₂₁, CH₂, O, S, SO, or SO₂; each Y₄ is, independently, Br, Cl, F,CN, CF₃, NO₂, N₃, OR₂₂, CO₂R₂₃, C₁₋₆alkyl, NR₂₄R₂₅, NHCOR₂₆, NHCO₂R₂₇,CONR₂₈R₂₉, or CH₂(CH₂)_(n)Y₂, or two adjacent Y₄ groups form a —O—CH₂—O—or —O—CH₂CH₂—O— group; p is 0, 1, 2,or 3; R₂₀ is hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, CH₂OR₃₀, or CH₂-aryl substituted by one or more Y₁substituents; each R₂₁ is, independently, hydrogen, C₁₋₈ alkyl, CH₂-arylsubstituted by one or more Y₁ substituents, NR₃₁R₃₂, NHCOR₃₃, NHCO₂R₃₄,CONR₃₅R₃₆, CH₂(CH₂)_(n)Y_(2,)or C(═NH)NR₃₇R₃₈; R₃₀ is hydrogen C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkenyl, CH₂O₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl, orCH₂-aryl substituted by one or more Y₁ substituents; R₂₂, R₂₃, R₂₄, R₂₅,R₂₆, R₂₇, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇ and R₃₈ are,independently, hydrogen, C₁₋₈ alkyl, CH₂-aryl substituted by one or moresubstituents OH, Br,Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; Z is N or S wherein when Z is S, there is no R₁₈; X₁ ishydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl; X₂ is hydrogen,C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl; or X₁ and X₂together form ═O,═S, or ═NH; or a pharmaceutically acceptable salt thereof.
 18. Themethod of claim 17, wherein R is OH, OC₁₋₃ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl substituted by one or moreY₁ groups, CH₂-aryl wherein the aryl group is substituted by one or moreY₁ groups, OCOC₁₋₄ alkyl, COC₁₋₄ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₄alkyl, or NHCO₂C ₁₋₄ alkyl; and Y₃ is hydrogen, Br, Cl, F, CF₃ NO₂, OR₈,CO₂R₉, C₁₋₃alkyl, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ orCH₂(CH₂)_(n)Y₂.
 19. The method of claim 17, wherein R is OH, OCH₃, orOCF₃; and Y₃ is hydrogen.
 20. The method of claim 17, wherein R₁, R₂, R₃and R₄ are each, independently, hydrogen, methyl or ethyl; and at leastone of R₁, R₂, R₃ and R₄ is other than hydrogen.
 21. The method of claim17, wherein R₁, R₂, R₃ and R₄ are each, independently, hydrogen ormethyl; and at least one of R₁, R₂, R₃ and R₄ is methyl.
 22. The methodof claim 17, wherein R is OH, OCH₃, or OCF₃; Y₃ is hydrogen; R₁, R₂,R₃and R₄ are each, independently, hydrogen, methyl or ethyl, wherein atleast one of R₁, R₂, R₃ and R₄ is other than hydrogen; and R₅ is—(CH₂)_(n)-phenyl, wherein n is
 3. 23. The method of claim 17, whereinR₅ is


24. The method of claim 17, wherein the opioid receptor antagonist isrepresented by the formula:

or a pharmaceutically acceptable salt thereof.
 25. A method of treatingdiabetes, diabetic complications, diabetic retinopathy,sexual/reproductive disorders, epileptic seizure, hypertension, cerebralhemorrhage, congestive heart failure, sleeping disorders,atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia,hypertriglycemia, hyperglycemia, hyperlipoproteinemia, substance abuse,drug overdose, compulsive behavior disorders and addictive behaviors,comprising administering to a subject in need thereof an effectiveamount of an opioid receptor antagonist represented by the formula (I):

wherein R is OH, OC₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl substituted by one or more Y₁ groups, CH₂-arylwherein the aryl group is substituted by one or more Y₁ groups, OCOC₁₋₈alkyl, COC₁₋₈ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₈ alkyl, or NHCO₂C₁₋₈alkyl; Y₃ is hydrogen, Br, Cl, F, CF₃, NO₂, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ or CH₂(CH₂)_(n)Y₂; R₁, R₂, R₃ andR₄ are each, independently, one of the following structures:

or R₁ and R₂, R₂ and R₃ and/or R₃ and R₄ are bonded together to form acyclo alkyl group or a bridged heterocyclic ring, wherein at least oneof R₁, R₂, R₃ and R₄ is other than hydrogen; each Y₁ is, independently,hydrogen, OH, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₈, CO₂R₉, C₁₋₆ alkyl,NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, or CONR₁₃R₁₄, or two adjacent Y₁ groups forma —O—CH₂—O— or —O—CH₂CH₂—O— group; each Y₂ is, independently, hydrogen,CF₃, CO₂R₉, C₁₋₈ alkyl,NR₁₀R_(11,)NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, CH₂OH,CH₂OR₈, COCH₂R₉,

each n is, independently, 0, 1, 2 or 3; each o is, independently, 0, 1,2 or 3; each R₈, R₉, R₁₀, R₁₁, R₁₂R₁₃ and R₁₄ is, independently,hydrogen, C₁₋₈ alkyl, CH₂-aryl wherein the aryl group is substituted byone or more substituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; each Y₂′ is, independently, hydrogen, CF₃, or C₁₋₆alkyl; R₅ is

 wherein n is 3,

 wherein n is 0, 1, 2 or 3,

 wherein n is 2 or 3,

 wherein n is 1, 2 or 3,

 wherein n is 0, 1, 2 or 3, —CH₂CH₂—X—R₆, or

R₆ is C₂₋₈ alkenyl, C₁₋₄ alkyl substituted C₄₋₈ cycloalkyl, C₁₋₄alkylsubstituted C₄-₈ cycloalkenyl, or thiophene; X is a single bond, —C(O)—or —CH(OR₁₅)—; R₁₅ hydrogen, C₁₋₆ alkyl, —(CH₂)_(q)-phenyl or —C(O)—R₁₆;R₁₆ is C₁₋₄ alkyl or —(CH₂)_(q)-phenyl; each q is, independently, 1, 2or 3; R₁₇is hydrogen, C₁₋₈ alkyl, CO₂C₁₋₈ alkylaryl substituted by oneor more Y₁ groups, CH₂-aryl substituted by one or more Y₁ groups, orCO₂C₁₋₈ alkyl; R₁₈ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈ alkynyl,CH₂CO₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl or CH₂-aryl substituted by one or moreY₁ groups; R₁₉, is a group selected from the group consisting ofstructures (a)-(p):

Q is NR₂₁, CH₂, O, S, SO, or SO₂; each Y₄ is, independently, Br, Cl, F,CN, CF₃, NO₂, N₃, OR₂₂, CO₂R₂₃, C₁₋₆ alkyl, NR₂₄R₂₅, NHCOR₂₆, NHCO₂R₂₇,CONR₂₈R₂₉, or CH₂(CH₂)_(n)Y₂, or two adjacent Y₄ groups form a —O—CH₂—O—or —O—CH₂CH₂—O— group; p is 0, 1, 2,or 3; R₂₀ is hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, CH₂OR₃₀, or CH₂-aryl substituted by one or more Y₁substituents; each R₂₁ is, independently, hydrogen, C₁₋₈ alkyl, CH₂-arylsubstituted by one or more Y₁ substituents, NR₃₁R₃₂, NHCOR₃₃, NHCO₂R₃₄,CONR₃₅R₃₆, CH₂(CH₂)_(n)Y_(2,)or C(═NH)NR₃₇R₃₈; R₃₀ is hydrogen C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkenyl, CH₂O₂C₁₋₈ alkyl, CO₂C₁₋₈ alkyl, orCH₂-aryl substituted by one or more Y₁ substituents; R₂₂, R₂₃,R_(24,)R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇ andR₃₈ are, independently, hydrogen, C₁₋₈ alkyl, CH₂-aryl substituted byone or more substituents OH, Br, Cl, F, CN, CF₃, NO₂, N₃, C₁₋₆ alkyl, orCH₂(CH₂)_(n)Y₂′; Z is N or S, wherein when Z is S, there is no R₁₈; X₁is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl; X₂ is hydrogen,C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl; or X₁ and X₂together form ═O,═S, or ═NH; or a pharmaceutically acceptable salt thereof.
 26. Themethod of claim 25, wherein R is OH, OC₁₋₃ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl substituted by one or moreY₁ groups, CH₂-aryl wherein the aryl group is substituted by one or moreY₁ groups, OCOC₁₋₄ alkyl, COC₁₋₄ alkyl, CONH₂, NHCHO, NH₂, NHSO₂C₁₋₄alkyl, or NHCO₂C ₁₋₄ alkyl; and Y₃ is hydrogen, Br, Cl, F, CF₃, NO₂,OR₈, CO₂R₉, C₁₋₃ alkyl, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄ orCH₂(CH₂)_(n)Y₂.
 27. The method of claim 25, wherein R is OH, OCH₃, orOCF₃; and Y₃ is hydrogen.
 28. The method of claim 25, wherein R₁, R₂, R₃and R₄ are each, independently, hydrogen, methyl or ethyl; and at leastone of R₁, R₂, R₃ and R₄ is other than hydrogen.
 29. The method of claim25, wherein R₁, R₂, R₃ and R₄ are each, independently, hydrogen ormethyl; and at least one of R₁, R₂, R₃ and R₄ is methyl.
 30. The methodof claim 25, wherein R is OH, OCH₃, or OCF₃; Y₃ is hydrogen; R_(l), R₂,R₃ and R₄ are each, independently, hydrogen, methyl or ethyl, wherein atleast one of R₁, R₂, R₃ and R₄ is other than hydrogen; and R₅ is—(CH₂)_(n)-phenyl, wherein n is
 3. 31. The method of claim 25, whereinR₅ is


32. The method of claim 25, wherein the opioid receptor antagonist isrepresented by the formula:

or a pharmaceutically acceptable salt thereof.